Traumatic brain injury (TBI) produces debilitating conditions that affect millions worldwide (Faul, et al., (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths. Atlanta (Ga.): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control). Recent data show that in the United States alone more than 1.7 million people, including military personnel, sustain a TBI every year (Faul, et al., (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths. Atlanta (Ga.): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; Fabrizio & Keltne, (2010) Traumatic brain injury in operation enduring freedom/operation Iraqi freedom: a primer. The Nursing Clinics of North America 45: 569-580, vi). Regardless of the severity of the trauma, motor, behavioral, intellectual and cognitive disabilities will be manifested as both short- and long-term (Ettenhofer & Abeles, (2009) The significant of mild traumatic brain injury to cognition and self-reported sympons in long term recovery from injury. J Clin Exp Neuropsychol. 31(3):363-72; Ozen & Fernandes, (2012) Slowing down after a mild traumatic brain injury: a strategy to improve cognitive task performance? Archives of clinical neuropsychology: the official journal of the National Academy of Neuropsychologists 27: 85-100; Werner & Engelhard, (2007) Pathophysiology of traumatic brain injury. British Journal of Anaesthesia 99: 4-9; Bath, et al., (2013) Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke. The Cochrane Database of Systematic Reviews 6: CD005207; Trivedi, et al., (2007) Longitudinal changes in global brain volume between 79 and 409 days after traumatic brain injury: relationship with duration of coma. Journal of Neurotrauma 24: 766-771; Greenberg, et al., (2008) Use of diffusion tensor imaging to examine subacute white matter injury progression in moderate to severe traumatic brain injury. Archives of Physical Medicine and Rehabilitation 89: S45-50). In moderate to severe trauma, TBI survivors present with chronic disabilities associated with loss of primary cerebral parenchymal tissues, secondary cell death including apoptosis, and exacerbated neuroinflammation (Ng, et al., (2008) Magnetic resonance imaging evidence of progression of subacute brain atrophy in moderate to severe traumatic brain injury. Archives of Physical Medicine and Rehabilitation 89: S35-44; Farbota, et al., (2012) Longitudinal volumetric changes following traumatic brain injury: a tensor-based morphometry study. Journal of the International Neuropsychological Society18: 1006-1018; Acosta, et al., (2013) Longterm upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One 8: e53376). Among the worst outcomes, sensorimotor dysfunctions, massive hippocampal cell death, learning and memory impairments, aphasia, anxiety, and dementia are the most prevalent (Smith, et al., (1998) Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. The American Journal of Pathology 153: 1005-1010; Coelho, (2007) Management of discourse deficits following traumatic brain injury: progress, caveats, and needs. Seminars in Speech and Language 28: 122-135; Azouvi, et al., (2009) Cognitive deficits after traumatic coma. Progress in Brain Research 177: 89-110; Bigler, (2013) Traumatic brain injury, neuroimaging, and neurodegeneration. Frontiers in Human Neuroscience 7: 395; Wong, et al., (2013) Factor structure of the Depression Anxiety Stress Scales in individuals with traumatic brain injury. Brain injury 27: 1377-1382). At present, clinical treatments are limited and the few that have been utilized have proven to be ineffective in most of the TBI cases (Cox, et al., (2011) Autologous bone marrow mononuclear cell therapy for severe traumatic brain injury in children. Neurosurgery 68: 588-600; Guan, et al., (2013) Transplantation of human mesenchymal stem cells loaded on collagen scaffolds for the treatment of traumatic brain injury in rats. Biomaterials 34: 5937-5946; Walker, et al., (2012) Bone marrow-derived stromal cell therapy for traumatic brain injury is neuroprotective via stimulation of non-neurologic organ systems. Surgery 152: 790-793). Preclinical studies have demonstrated that adult stem/progenitor cells transplantation is a promising therapeutic intervention for TBI (Maegele & Schaefer, (2008) Stem cell-based cellular replacement strategies following traumatic brain injury (TBI). Minimally Invasive Therapy & Allied Technologies 17: 119-131; Sanberg, et al., (2012) Advantages and challenges of alternative sources of adult-derived stem cells for brain repair in stroke. Progress in Brain Research 201: 99-117). Bone marrow stromal cells (BMSC), adipose derived stem cells (ADSC), amniotic fluid stem cells (AFSC) and the mononuclear fraction of human umbilical cord blood (hUCB) have shown neuroprotective properties by decreasing inflammation, brain tissue loss, promoting neurogenesis, and rescuing neurological functions such as learning and memory in experimental models of chronic TBI (Maegele & Schaefer, (2008) Stem cell-based cellular replacement strategies following traumatic brain injury (TBI). Minimally Invasive Therapy & Allied Technologies 17: 119-131; Sanberg, et al., (2012) Advantages and challenges of alternative sources of adult-derived stem cells for brain repair in stroke. Progress in Brain Research 201: 99-117; Kim, et al., (2010) Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. Journal of Neurotrauma 27: 131-138; Mahmood, et al., (2006) Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats. Journal of Neurosurgery 104: 272-277; Tajiri, et al., (2012) Intravenous grafts of amniotic fluid-derived stem cells induce endogenous cell proliferation and attenuate behavioral deficits in ischemic stroke rats. PLoS One 7: e43779). However, the injured micro-environment limits their regenerative potential (Walker, et al., (2012) Bone marrow-derived stromal cell therapy for traumatic brain injury is neuroprotective via stimulation of non-neurologic organ systems. Surgery 152: 790-793; Tu, et al., (2012) Combination of temperature-sensitive stem cells and mild hypothermia: a new potential therapy for severe traumatic brain injury. Journal of Neurotrauma 29: 2393-2403). For instance, TBI victims suffer from brain oxygen depletion, vasogenic edema, and secondary injury signals including reactive oxygen species, exacerbated activated MHCII+ cells, astrogliosis and pro-inflammatory cytokines such as, but not limited to, IL-1β and TNF-α, which can accumulate in the area of injury leading to decreased survival of transplanted adult stem cells (Acosta, et al., (2013) Longterm upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One 8: e53376; Tu, et al., (2012) Combination of temperature-sensitive stem cells and mild hypothermia: a new potential therapy for severe traumatic brain injury. Journal of Neurotrauma 29: 2393-2403; Ghirnikar, et al., (1998) Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochemical Research 23: 329-340). The use of combined therapies stands as a promising technique to overcome molecular aberrations while enhancing the adult stem cells' therapeutic potential in chronic TBI (Campbell, et al., (2013) Efficacy of mild hypothermia (35 degrees C.) and moderate hypothermia (33 degrees C.) with and without magnesium when administered 30 min post-reperfusion after 90 min of middle cerebral artery occlusion in Spontaneously Hypertensive rats. Brain Research 1502: 47-54; Mahmood, et al., (2013) Effects of treating traumatic brain injury with collagen scaffolds and human bone marrow stromal cells on sprouting of corticospinal tract axons into the denervated side of the spinal cord. Journal of Neurosurgery 118: 381-389).
Colony stimulating factors (CSF), also called haemopoietic growth factors, regulate the mobilization, proliferation, and differentiation of bone marrow cells. Growth factors such as granulocyte colony stimulating factor (G-CSF), granulocytes-macrophages colony stimulating factor (GM-CSF), colony stimulating factor-1 (CSF-1), and erythropoietin are currently being investigated as therapeutics for cancer, certain autoimmune diseases, ischemic insults and neurodegenerative diseases (Farbota, et al., (2012) Longitudinal volumetric changes following traumatic brain injury: a tensor-based morphometry study. Journal of the International Neuropsychological Society18: 1006-1018; Lyman, et al., (2013) The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Annals of Oncology 24: 2475-2484; Sanchez-Ramos, et al., (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 163: 55-72). Recent evidence suggests that G-CSF affords beneficial effects against central nervous system (CNS) conditions such as stroke and Alzheimer's disease (Sanchez-Ramos, et al., (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 163: 55-72; Sanchez-Ramos, et al., (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 163: 55-72; Cui, et al., (2013) Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke. PLoS One 8: e64684; Prakash, et al., (2013) Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-beta induced experimental model of Alzheimer's disease. Pharmacology, Biochemistry, and Behavior 110: 46-57). Short-term treatment of systemic G-CSF significantly improved cognition accompanied by reduced central and peripheral inflammation, enhanced neurogenesis and decreased the amyloid deposition in the hippocampus and entorhinal cortex in both mice and rats experimental models of Alzheimer's disease (Sanchez-Ramos, et al., (2009) Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice. Neuroscience 163: 55-72; Prakash, et al., (2013) Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-beta induced experimental model of Alzheimer's disease. Pharmacology, Biochemistry, and Behavior 110: 46-57). Similarly, G-CSF, together with stem cell factor, restored neural circuits by facilitating anatomical connections of dendritic spines and branches with the adjacent infarcted area of experimental stroke (Cui, et al., (2013) Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke. PLoS One 8: e64684). Recent clinical trials of G-CSF treatment in stroke patients have been proven safe (England, et al., (2012) Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial. Stroke 43: 405-411), but efficacy remains inconclusive (Farbota, et al., (2012) Longitudinal volumetric changes following traumatic brain injury: a tensor-based morphometry study. Journal of the International Neuropsychological Society18: 1006-1018).
As such, what is needed is a novel treatment option that can show effective therapy to traumatic brain injury for extended periods of time.